tbuckley/cabot-search huggingface dataset:
QOL-10. NOVEL MULTIMODAL STUDY OF THREE COGNITIVE REHABILITATION INTERVENTIONS IN LOWER GRADE GLIOMA
Authors: Christina Weyer Jamora, Melissa Brie, Paige Bracci, Ellen Smith, Tracy Luks, Stephanie Phan, Steve Braunstein, Javier Villanueva-Meyer, Karen Gehring, Adrian Aguilera, Nancy Ann Oberheim Bush, Nicholas Butowski, Jennifer Clarke, Mariza Daras, John de Groot, Susan M Chang, Shawn L Hervey-Jumper, Jennie Taylor
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Grade 2 and 3 glioma survivors (LrGG) are living longer, yet experience cognitive impairments with diminished quality of life (QOL). We present a novel multimodal study of three cognitive rehabilitation interventions in stable LrGG survivors. METHODS Participants were radiologically stable adult LrGG patients who were off medical treatment for ≥ 6 months with subjective and objective cognitive impairments ( &amp;gt;1SD in 2 or more domains). Patients were offered either In-person cognitive rehabilitation (strategy training including telehealth), or randomized to App-based cognitive rehabilitation (retraining and strategy training) versus Text messaging (strategy training). Intervention duration was 3 months. Neuropsychological testing (with parallel forms) and QOL assessments were conducted at baseline (T1), immediate post intervention (T2), and 6-month follow-up (T3), and analyzed with repeated measures regression or Wilcoxon signed rank tests. RESULTS Of the 33 analyzed (enrollment ongoing); 15/17 In-person, 5/8 App-based, and 8/8 Texting completed ≥ 80% or greater of interventions. Demographic and clinical characteristics were similar between cohorts. Median age was 48 years (range 27-63), 58% astrocytoma, 30% oligodendroglioma, 15% other (1 pilocytic astrocytoma, 4 diffuse glioma NOS), and 76% had prior radiotherapy. Rehabilitation interventions showed improvements in auditory working memory (T1-T2 In-person p= 0.02, eta2= 0.32-medium effect), verbal learning (T1-T3 App-based p= .06, eta2= 0.54-large effect; T1-T3 Texting p= .01, eta2= 0.75-large effect), and verbal memory (T1-T3 App-based p= .06, rho=0.31-medium effect). CONCLUSION Significant improvements in cognitive impairments were found with medium to large treatment effects within each cohort. Cognitive rehabilitation via In-person and Texting showed strongest feasibility and acceptability. In-person cognitive rehab showed earlier posttreatment improvements whereas treatment effects for App-based and Texting were noted, but took longer to realize gains. These interventions may show promise for addressing cognitive impairments in LrGG survivors and warrant further investigation.
CSIG-04. BMP4 INDUCTION OF A SENESCENCE-LIKE PHENOTYPE IN HUMAN GLIOBLASTOMA CELLS IS PARTIALLY DEPENDENT ON P21
Authors: Mia Niklasson, Erika Dalmo, Bengt Westermark
Journal: Neuro-Oncology (2022)

Abstract Bone morphogenetic protein 4 (BMP4) was initially suggested as a potential differentiation-inducing factor to be used in the therapy of glioblastoma. We and others have however demonstrated that the response is reversible, variable among patient samples, and heterogeneous within the same cell line. To deepen our knowledge on how BMP4 affects different types of glioblastoma cells, we treated phenotypically different clones from the same patient tumor—a multitherapy-sensitive/proneural-like (SENS/PN) clone and a multitherapy-resistant/mesenchymal-like (RES/MES) clone—with BMP4. In the SENS/PN clone, BMP4 turned on a mesenchymal-related gene program, whereas this response was less prominent in the RES/MES clone. Untreated SENS/PN cells were smaller than RES/MES cells, but both clones responded to BMP4 by cell size enlargement. Increase in cell size has been suggested to precede senescence; young cells are smaller than old cells that eventually enter replicative senescence. BMP4 induced a senescence-like phenotype in a subpopulation of cells, demonstrated by induction of senescence-associated (SA)-β-gal, p21 up-regulation, lamin B1 down-regulation, as well as increased lysosomal mass and granularity. This was more pronounced in the RES/MES clone than in the SENS/PN clone, and it was dependent on canonical SMAD signaling. Senolytic treatment ablated the SA-β-gal positive cells and reduced the p21 level at the population level. Targeted deletion of p21 abolished BMP4-induced SA-β-gal and increase in cell growth, while lamin B1 down-regulation remained, demonstrating that p21 signaling is crucial for one part of the senescence induction by BMP4. We are currently further investigating a connection between cell size, mesenchymality and senescence. We hypothesize that large mesenchymal-like cells are closer to senescence than smaller proneural cells within the cell culture. A combination of senescence-induction and senolytic treatment may open treatment opportunities to target therapy-resistant glioblastoma cells.
TMET-37. SODIUM-DEPENDENT GLUCOSE TRANSPORTER 2 (SGLT2) IS OVEREXPRESSED IN THE MAJORITY OF ATRTS AND A SUBSET OF PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMA; A POTENTIAL IMAGING AND THERAPEUTIC TARGET
Authors: Ali Nabavizadeh, Chao Zhao, Daniel Martinez, Ariana Familiar, Mateusz Koptyra, Joseph Ippolito, Joshua Rubin, Philip B Storm, Adam C Resnick, Mariarita Santi
Journal: Neuro-Oncology (2022)

Abstract Sodium glucose cotransporters (SGLT) are a class of glucose transporters independent of the conventional glucose transporters (GLUT). Like the GLUT, SGLT2 plays an important role in glucose uptake in many solid cancers. Importantly, SGLT2 inhibitors are a new class of anti-diabetic drugs and have recently been investigated as a potential anti-cancer therapy in a variety of solid cancers. In fact, a recent study in adult high-grade gliomas showed that an SGLT-specific PET imaging probe ([18F] Me-4FDG) is sensitive for visualization of high-grade glioma (HGG) with superior tumor-normal brain uptake relative to 18F-FDG-PET. We aimed to investigate the expression of SGLT2 within pediatric brain tumor subtypes using RNA sequencing data from PedcBioPortal and immunohistochemistry of tissue microarrays (TMAs). Using the RNA sequencing data from 603 patients with pediatric brain tumors, we found that HGGs have the highest SGLT2 expression (Z score=0.13± 1.03) and were significantly higher compared to low-grade gliomas (Z score= -0.12, p=0.049), medulloblastomas (Z score=-0.28, p=0.001), and ependymomas (Z score=-0.30, p=0.002). Atypical teratoid rhabdoid tumors (ATRT) also had significantly higher Z score (0.10±0.67) compared to medulloblastomas (p=0.038), and ependymomas (p=0.049). There was no significant difference between HGGs and ATRTs in SGLT2 expression (p=0.899). Analysis of 4 TMAs including HGGs, medulloblastomas, ependymomas, and ATRTs after SGLT2 immunohistochemistry demonstrated strong membranous staining in a small subset and moderate-weak staining in the majority of HGGs. The majority of ATRTs were positive. The majority of medulloblastomas and ependymomas were negative, noting that the membranous nature of the staining may be a limiting factor in evaluation of tumors with less cytoplasm. In conclusion, our work demonstrates that SGLT2 has heterogeneous expression in pediatric brain tumors and is overexpressed in the majority of ATRTs, and a subset of pediatric HGGs, and may represent a compelling paradigm that integrates metabolic imaging and therapy of these tumors.
CTNI-29. INVESTIGATING SAFETY AND EFFICACY OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA - FIRST RESULTS OF THE PRICOTTF PHASE I/II TRIAL
Authors: Sied Kebir, Lazaros Lazaridis, Teresa Schmidt, Christoph Oster, Jonas Feldheim, Daniela Pierscianek, Martin Proescholdt, Peter Hau, Anca-Ligia Grosu, Dietmar Krex, Ulrich Sure, Björn Scheffler, Christoph Kleinschnitz, Christoph Pöttgen, Martin Stuschke, Martin Glas
Journal: Neuro-Oncology (2022)

Abstract Background A synergistic inhibiting effect on glioblastoma cell proliferation was reported for the combination of TTFields and radiotherapy. Based on these preclinical findings, we performed the phase I/II PriCoTTF trial in adult nGBM patients to investigate the safety and efficacy of TTFields therapy initiated prior and concomitant to radiochemotherapy. MATERIAL AND METHODS In this phase I/II trial, TTFields therapy was initiated following surgery and continued throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. TTFields rechallenge was allowed at recurrence. Radiotherapy was conducted with arrays applied on the patients’ scalp. Safety and tolerance are the study’s primary endpoint, determined by a selection of pre-specified treatment-limiting toxicities (TLTs). RESULTS A total of 33 patients have been enrolled. Patients' characteristics were mostly typical for glioblastoma, except for a rather low fraction of patients with gross total resection (GTR, 22.5%). The distribution of adverse events of ≥ common toxicity criteria (CTC) grade 3 was comparable to that of established glioblastoma trials. Notably, skin toxicity of ≥ CTC grade 3 was uncommon (n = 2, 6%). No patient developed TLTs. Median TTFields treatment duration was 8.4 months. Overall survival data was not mature enough (event rate 48%) to allow for a definite conclusion Notably, on multivariable Cox regression, the number of days with TTFields adherence &amp;gt; 23 hours was independently associated with overall survival (HR 0.96, 95% confidence interval 0.93 - 0.99, p = 0.008). CONCLUSION The PriCoTTF trial met its primary endpoint indicating that combined TTFields and radiotherapy is safe and well tolerated. High-grade skin toxicity was quite uncommon and the patients with high TTFields adherence seem to perform particularly well. An extended follow-up is required to provide first estimates regarding putative efficacy. At that point in time, the reduced overall TTFields duration and fraction of patients with GTR need to be factored in.
RADT-14. COMBINATION RE-RADIATION AND BEVACIZUMAB THERAPY FOR RECURRENT GLIOBLASTOMA: CLINICAL OUTCOMES OF 337 PATIENTS
Authors: Mahlet Mekonnen, Khashayar Mozaffari, Othneil Sparks, Amith Umesh, Ashley Bo Zhang, Isaac Yang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND High-grade gliomas (HGGs) comprise the most common primary adult brain cancers and universally recur. Glioblastoma (GBM) compromise 60% of HGGs with an extremely poor prognosis and are considered incurable despite many treatment advancements. Combination re-radiation therapy (re-RT) and bevacizumab (BVZ) therapy for recurrent HGG is commonly used, however, there is a paucity of literature with respect to its efficacy. OBJECTIVE This study aimed to compare treatment outcomes of patients who received reRT alone versus a combination of reRT and BVZ (reRT ± BVZ ) to establish clear guidelines for the optimal management of recurrent GBM. METHODS We identified patients with recurrent GBM treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality. Primary outcomes of interest included radiation necrosis (RN), progression-free survival (PFS), and overall survival (OS). These parameters were then compared between the reRT + BVZ and the reRT alone cohorts. RESULTS A total of 337 patients were included. Mean age at primary resection was 51 years old (range: 5-82). Of those, 223 (66.2%) were male and 114 (33.8%) were female. All patients were initially treated with surgical resection. Mean follow up for the entire cohort was 19.1 months (± 1.14 months). The re-RT + BVZ cohort had a longer median survival at 14 months with 6-, 12-, and 24- month survivals of 84%, 60%, and 19.4%, respectively compared to their re-RT alone counterparts. Our study suggests that the combination of reRT+BVZ is effective in improving overall survival and lowering radiation necrosis rates, compared to reRT alone. CONCLUSIONS Combination reRT+BVZ may improve OS and reduce rates of RN in recurrent GBM, but further controlled studies are warranted to validate these effects. Future studies should investigate optimal protocols for reRT+BVZ treatment, and for evaluating subsequent radiologic progression in patients with recurrent GBM.
CTNI-59. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Richard Green, Colleen Thornton, Ruben Guzman
Journal: Neuro-Oncology (2022)

Abstract We report our experience treating 22 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 64 y (range 45-85); 10 patients were men and 12 were women. Twenty had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 16 patients completed initial chemotherapy. Fourteen of these 16 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One patient who completed the entire regimen including transplantation died of fungal pneumonia and the other 13 experienced no serious acute toxicity. One patient had late disease progression and one developed symptomatic leukoencephalopathy. Fourteen of the 22 patients remain alive. Median OS for the cohort is 663 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y suggests that the regimen may be too toxic for older individuals.
TMET-07. MOLECULAR MECHANISM OF EXQUISITE SENSITIVITY OF DIFFUSE MIDLINE GLIOMA TO DE NOVO PYRIMIDINE BIOSYNTHESIS
Authors: Sharmistha Pal, Milan Savani, Jakub Kaplan, Sylwia Sylwia A Stopka, Huy Nguyen, Michael Regan, Nathalie Agar, Samuel McBrayer, Daphne Haas-Kogan
Journal: Neuro-Oncology (2022)

Abstract Diffuse midline glioma (DMG) is a lethal pediatric brain cancer in dire need for therapeutic breakthroughs. To identify intrinsic addictions and therapeutic targets for DMG, we conducted a genome-wide k¬¬¬¬nockout CRISPR screen that identified de novo pyrimidine biosynthesis pathway as a targetable dependency. Since pyrimidine nucleotides can be synthesized by salvage and de novo pathways, identification of the latter as a dependency indicated a prominent role of de novo pathway in establishing the pyrimidine nucleotide pool in DMG. We investigated the molecular mechanism underlying this dependency using metabolic tracing of 15N-glutamine and genetic approaches. We report that DMG cells derive the majority of UMP (70%) through de novo synthesis, along with significantly elevated flux through the pyrimidine degradation pathway. High flux of 15N- labeled UMP through pyrimidine degradation in DMGs suggests that substrates (uridine and uracil) required for pyrimidine nucleotide salvage are limited, thus enhancing the dependency on de novo biosynthesis. To further confirm the causal role of pyrimidine degradation in driving de novo pathway dependency in DMG, we knocked down DPYD, the enzyme catalyzing the first committed step in pyrimidine degradation, using inducible shRNAs. Knockdown of DPYD diminished sensitivity of DMGs to de novo pathway inhibition as it rescued UMP pools and resultant DNA damage. Conversely, overexpression of DPYD in adult glioblastomas enhanced their sensitivity to de novo pyrimidine synthesis inhibition which was accompanied by greater depletion of UMP and induction of DNA damage. Consistent with this mechanism, we observed downregulation of DPYD in DMGs that acquired resistance to antagonists of de novo pyrimidine synthesis. Taken together, we have uncovered DPYD as a predictive biomarker of sensitivity to de novo pyrimidine synthesis inhibitors.
CTNI-64. FOCUSED ULTRASOUND MEDIATED BLOOD-BRAIN BARRIER PENETRANCE TO ENABLE CELL-FREE DNA (CFDNA) AS A LIQUID BIOPSY IN RECURRENT PRIMARY BRAIN TUMORS
Authors: Alexandra Miller, Bhaskar Ramamurthy, Luke Pike, Mallika Keralapura, Jonathan Hofius, Jack Marshall, Marvin Jones, Chi-Yin Lee, Joseph Stember, Cameron Brennan, Thomas Kaley, Ryan Dittamore, Ingo Mellinghoff
Journal: Neuro-Oncology (2022)

Abstract The WHO recommends molecular characterization of CNS tumors. (Louis et al., 2021, 2016). However, many patients at diagnosis and recurrence, do not have tissue accessible for genomics. Blood-based liquid biopsy tests, provide a non-invasive means to obtain genomic data. Liquid biopsy tests are widely adopted to avoid side effects related to invasive biopsies in other solid tumors. However, for primary brain tumors, most patients have cfDNA concentrations below the Limit-of-Detection (LOD) of the tests. The primary contributor to low yield is the blood-brain barrier (BBB) which prevents free passage of tumor analytes into the circulatory system. BBB opening mediated by Focused Ultrasound (FUS) oscillation of microbubbles (MB) has led to an increase of tumor-derived circulating biomarkers in pre-clinical models and in human GBM (Zhu et al 2018, Meng et al 2021). Cordance Medical is developing a non-invasive, portable FUS platform that can enable clinic-based BBB opening treatments. The Cordance device utilizes three transducer types, a Type 1 transducer for non-invasive BBB opening localization obtains Doppler images of the Circle-of-Willis through the temporal lobe. The Doppler images align to the existing MRI using CoW as the fiducial. An array of Type 2 transducers for BBB opening to generate sufficient acoustic pressure to safely oscillate MBs to open the BBB. Finally, Type 3 transducers for safety monitoring receive echo signals from the MBs. Signals are analyzed for harmonic content which enables safety monitoring. The primary endpoint, we will be examining the Cordance platform's ability to increase the concentration of circulating biomarkers following a safe BBB opening. We will recruit patients with recurrent GBM. Patients will receive a baseline blood draw, a BBB opening treatment with the Cordance device, followed by a blood draw after the treatment. Liquid biopsy tests to be examined include the MSK ACCESS test and tumor-informed ddPCR MRD test.
CTIM-03. PEMBROLIZUMAB MONOTHERAPY FOR MICROSATELLITE INSTABILITY-HIGH (MSI-H) OR MISMATCH REPAIR DEFICIENT (DMMR) RECURRENT GLIOMAS: RESULTS FROM THE MULTICOHORT PHASE 2 KEYNOTE-158 STUDY
Authors: Capucine Baldini, Philippe A Cassier, Jean-Pierre Delord, Matteo Simonelli, Mehdi Touat, Lili Yao, J Paul Duic, Alexander Gozman, Aurelien Marabelle
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Patients with recurrent glioma have limited treatment options. The anti‒ PD-1 monoclonal antibody pembrolizumab demonstrated antitumor activity as monotherapy in a subset of patients with PD-L1–positive recurrent glioblastoma (GBM) in the KEYNOTE-028 study; and durable clinical benefit in patients with previously treated unresectable/metastatic MSI-H/dMMR non-colorectal tumors in the multicohort KEYNOTE-158 (NCT02628067) study. We report outcomes with pembrolizumab in patients with MSI-H/dMMR recurrent glioma enrolled in KEYNOTE-158. METHODS Adults with MSI-H/dMMR recurrent glioma, measurable disease per RECIST v1.1, ECOG PS 0/1, and tumor sample for biomarker analysis were eligible for cohort K (any MSI-H/dMMR advanced solid tumor, except colorectal cancer; local, prospective determination of MSI-H/dMMR status by PCR and/or IHC). Patients received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD/unacceptable AEs (clinically stable patients could continue treatment until PD confirmed after ≥ 4 weeks). Primary endpoint was ORR per RECIST v1.1 by independent central review. RESULTS Among 21 enrolled patients, all received prior temozolomide, 12 (57%) received prior bevacizumab, and 14 (67%) received ≥ 2 prior lines of therapy. 14 (67%) patients had GBM, 4 (19%) had oligodendroglioma/oligoastrocytoma, and 3 (14%) had glioma NOS. Median time from first dose to data cutoff (January 12, 2022): 50.0 months; 19 (90%) patients discontinued treatment. 1 patient with GBM had PR (ORR, 4.8% [95%CI, 0.1%‒23.8%]); duration of response was 18.9 months, PFS 29.2 months, and OS 32.7 months. 3 (14%) patients had SD; PFS was 23.2, 14.5, and 3.3 months; OS was 23.2, 15.1, and 9.1 months. Overall, median PFS and OS (95%CI) were 1.4 (1.0‒2.1) months and 5.6 (2.6‒16.2) months. Treatment-related AEs occurred in 7 (33%) patients (grade 3/4, n = 1; no grade 5) and led to discontinuation in 1 (5%) patient. CONCLUSIONS Pembrolizumab demonstrated antitumor activity with manageable toxicity in a small subset of patients with relapsing/refractory MSI-H/dMMR glioma.
SURG-22. STAGED LASER INTERSTITIAL THERAPY (LITT) FOR THE SURGICAL TREATMENT OF INSULAR GLIOMA: A CASE SERIES WITH A NOVEL TREATMENT PARADIGM
Authors: Hassan Fadel, Jacob Pawloski, Sameah Haider, Adam Robin, Ian Lee
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Insular gliomas pose a significant surgical challenge due to the insula’s delicate surrounding functional and vascular anatomy. Insular gliomas are conventionally treated with open surgical resection augmented by several surgical adjuvants. Despite advancements in technology and surgical techniques, surgical resection of insular gliomas has been associated with frequent and potentially severe morbidity. Laser interstitial thermal therapy (LITT) is a novel, cytoreductive, and less-invasive treatment option for glioma. OBJECTIVE We describe the first-ever series of patients with insular glioma treated with staged LITT with or without subsequent craniotomy. METHODS A retrospective institutional database identified patients with insular glioma who underwent staged LITT treatments. Clinical, histopathological, and volumetric lesional characteristics were obtained. Procedural characteristics, morbidity, overall survival (OS), and progression-free survival (PFS) were determined. RESULTS Between 2019-2022, 11 patients with insular glioma were treated in stages with a total of 21 LITT procedures with or without subsequent craniotomy. Four patients had Diffuse Astrocytoma (IDHmt/TP53+), one Gemistocytic Astrocytoma (IDHmt/TP53+), three Anaplastic Astrocytoma (IDHmt/TP53+), one Anaplastic Oligodendroglioma (IDHmt/1p19q codel), one secondary GBM (IDHmt/TP53+), and one GBM (IDHwt/TP53-). Six patients were treated with LITT alone, while five patients were treated with LITT followed by a craniotomy for complete resection. Patients had a median tumor volume of 31.5 cm3 (9.58, 97) and a mean extent of ablation±resection of 97.68% (S.D. 5.4). At a median follow-up of 12.59 months, patients had a median PFS of 12.88 months and an OS of 14.46 months. No patients had a change in KPS following LITT. Two patients had a decrease in KPS following surgery. CONCLUSION We present the first-ever reported series of insular glioma treated with staged LITT with/without subsequent resection. We found that staged treatment of insular gliomas with LITT is safe, effective, and a minimally invasive option that avoids the potentially significant morbidity associated with conventional surgery.